Dr.P.Subramani II year Postgraduate SRMC. Dr.Latha Ravichandran Professor Department of pediatrics

Transcription

1 Dr.Latha Ravichandran Professor Department of pediatrics Dr.Julius Xavier Scott Professor Department of pediatric hematooncology Sri Ramachandra University, Porur. Dr.P.Subramani II year Postgraduate SRMC

2 CASE HISTORY 3 months old, Girl infant History of hypopigmentation over the skin x 1 month Recurrent respiratory tract infection x 1 month Fever x 3 days Loose stools x 2 days

3 GENERAL EXAMINATION Febrile (Temp F). Vitals stable Anthropometry: Normal Pallor present. Blond hair Intermittent areas of skin hypopigmentation over face, trunk and limbs Cervical and axillary lymph nodes palpable.

4 SYSTEMIC EXAMINATION Spleen 3 cm below left costal margin. Liver 1 cm below right costal margin. Other systems- NAD.

5 PROBLEM LIST Fever Splenohepatomegaly Hypopigmentation Blond hair Recurrent infections

6 DIFFERENTIAL DIAGNOSIS DD 1. IEM RULED OUT Urine for metabolic screening :NEGATIVE 2. TORCH infection TORCH panel: NEGATIVE 3. Immunodeficiency Immunoglobulin Assay : NORMAL Further workup was planned.

7 INVESTIGATIONS INVESTIGATIONS INVESTIGATION Hb Hb Total Total count count L Lymphocytes PCV MCV MCV Platelets Platelet RFT/serum BUN electrolytes S.Creatinine LFT/coagulati Peripheral on profilesmear REPORT REPORT 6.6g/dl 6.6g/dl 5900/cu.mm 5900/cu.mm ,000 60,000 INVESTIGATION INVESTIGATION Serum electrolytes Uric acid Uric acid LDH REPORT REPORT NORMAL PT/PTT/INR NORMAL DCT LDH NEGATIVE 735 S.G.O.T 146 S.G.P.T 70 Serum ferritin 2734 Normal 15 Triglycerides DCT 323mg/dl NEGATIVE 0.5 Normal CXR and Xray TOTAL BILIRUBIN 0.87 Microcytic, thromocytopenic Skull, USG abdomen CXR Normal NAD

8 SUSPICION OF HLH HLH CRITERIA OUR CASE Fever Fever Splenomegaly Cytopenia ( more than or 2 cell lineages) Hypertriglyceridemia/ Splenomegaly Bicytopenia Hypofibrinogenemia Hyperferritinemia Low/Absent NK cell activity Hemophagocytosis Elevated soluble CD25 Hypertriglyceridemia - 323mg/dl Hyperferritinemia HLH?Familial? Secondary to infection

9 Hypo HLH pigmentation MISSING LINK Recurrent infection? Blond hair

10 PERIPHERAL SMEAR RBC: Microcytic hypochromic with anisocytosis WBC: Few reactive lymphocytes Few lymphocytes showing large abnormal granules PLATELET COUNT: Thrombocytopenia

11 Hypo HLH Pigment \Blond hair CHS Accelerated phase Recurrent infections PS- Granules

12 BONE MARROW 1. Hemophagocyte 2. Large Granules SKIN BIOPSY 1. Irregulary arranged large melanosomes.

13 MANAGEMENT Control infection IV Piperacillin/Tazobactum, Amikacin Stepped up to Meropenem IV fluconzole To find the source of infection Blood &Urine C/S- NO GROWTH

14 Further Treatment Plan. Ophthalmology evaluation : Not suggestive of occular albinism Parents were counselled about the prognosis Genetic counselling given. Planned to continue IV antibiotics for a week Dexamethasone + Etoposide and intravenous immunoglobulin thrice weekly (HLH 2004 PROTOCOL) Referral to transplant physician

15 Parents were not willing for any further approach of treatment and wanted to continue with the conservative plan of management. Child succumbed to illness 2 days post discharge.

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17 CHEDIAK HIGASHI SYNDROME Rare autosomal recessive disorder characterized by Ø Recurrent pyogenic infections, Ø Partial oculocutaneous albinism, Ø Progressive neurologic abnormalities, Ø Mild coagulation defects, Ø A lymphoma-like accelerated phase Less than 500 cases have been reported worldwide. First case in India reported in 1982 *Chediak-Higashi syndrome. Kaplan J, De Domenico I, Ward DM Curr Opin Hematol. 2008;15(1):22.

18 PATHOGENESIS Mutation in the lysosomal trafficking regulator (CHS1/LYST) gene at 1q42 Abnormal organellar protein trafficking Aberrant fusion of vesicles Failure to transport lysosomes to the appropriate site of action Altered lysosomes/granules are found in all cell types in CHS, and are the hallmark of the disease * Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nagle DL, Karim MA, Woolf EA, Holmgren L. Nat Genet. 1996;14(3):307.

19 Defective neutrophil chemotaxis, degranulation and bactericidal activity. Giant granules Interfere with the cells ability to traverse the narrow passages between endothelial cells into tissue. RECURRENT INFECTIONS Impaired NK cell function Pathologic aggregation and uneven distribution of melanosomes Impaired Platelet Aggregation HYPOPIGMENTATION MILD BLEEDING DIATHESIS

20 CLINICAL MANIFESTATIONS Partial oculocutaneous albinism Hepatosplenomegaly and Recurrent pyogenic infections Mild coagulation defect lymphadenopathy. Ocular manifestations Gingivitis, oral ulcerations, and periodontal disease. include photophobia, decreased visual acuity, nystagmus, and strabismus. About 10 percent of patients survive early childhood despite serious infections, but develop severe, debilitating neurologic manifestations in adolescence and early adulthood

21 DIAGNOSIS Peripheral blood smear for the classic large granules in all nucleated giant cells. Examination of skin melanocytes reveals giant melanosomes. Genetic testing for mutations in the CHS1/LYST gene. Light microscopy of hair shafts shows small aggregates of clumped pigmentation that are irregularly distributed. CHS can be diagnosed prenatally by examining amniotic or chorionic villus cells for enlarged lysosomes.

22 ACCELERATED PHASE Lymphohistiocytic infiltration of virtually all organ systems. Even more profound immune deficiency. Patients present with fever, increased hepatosplenomegaly and lymphadenopathy, and worsened pancytopenia and bleeding. This phase occurs in more than 80 percent of patients and is usually lethal.

23 MANAGEMENT Supportive High dose Ascorbic acid improves the clinical status in stable phase- Controversy. IV antibiotics for infections. CURATIVE THERAPY : Stem Cell Transplant

24 MANAGEMENT INITIAL 8 WEEKS CHEMOTHERAPY FAMILIAL Etoposide Dexamethasone PERSISTANT Non-Familial HSCT Re activation IT Methotrexate (after 2 weeks when progressive neurological symptoms) RESOLVED Non-Familial Accelerated Phase : HLH 2004 protocol. Stop Therapy

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26 Chediak Higashi Syndrome presenting in Accelerated phase Tanzeel Imran, Lybna Zafar, Madeeha Rehan Journal of college of Physicians and surgeons Pakistan 2012 A 2 year old boy presented with high grade fever, cough, swelling of neck and abdominal distention. pallor, hepatosplenomegaly significant cervical lymphadenopathy,enlarged axillary and inguinal lymph nodes. He also had silver hair and partial cutaneous albinism since birth. Bone marrow aspirate also revealed prominent histiocytes and haemophagocytosis. On the basis of his clinical presentation, peripheral blood film and bone marrow aspirate findings, the diagnosis of Chediak-Higashi syndrome was established. Unfortunately patient expired after 24 days of hospital stay.

27 Chédiak-higashi Syndrome: An Accelerated Phase With Hereditary Elliptocytosis Abu Sharif M. A. Islam, MD; Zakaria M. Hawsawi, MD; Annals of Saudi Medicine, Vol 21, Nos 3-4, year-old male, blond hair and patchy cutaneous hypopigmentation, H/O recurrent Respiratory tract infections. Blood reports revealed features of HLH. Peripheral smear, Bone marrow confirmed Chediak Higashi Syndrome. Bone marrow transplantation was performed. Boy clinically well.

28 Chediak higashi can present with Oculo Cutaneous albinism, Splenomegaly, Lymphadenopathy, Fever and H/O recurrent infections. Carefully examined peripheral smear can clinch the diagnosis. Accelerated phase of CHS presents as HLH. Since the disease is usually lethal in the first decade, its early detection may facilitate early BMT, which is the only curative approach.

29 THANK YOU!!